Objective: Serum antibodies against the glial potassium channel KIR4.1 are found in a subpopulation (5-50% depending on who you believe see below) of multiple sclerosis (MS) patients. Little is known about the expression of KIR4.1 in human normal brain tissue and in MS lesions.

Methods: We analyzed the expression pattern of KIR4.1 in normal brain tissue and MS lesions of the subcortical white matter by immunohistochemistry. Markers of related glial proteins, myelin and inflammatory cells were analyzed in parallel.

Results: KIR4.1 is expressed in oligodendrocytes and astrocytes in the adult human brain. In oligodendrocytes, KIR4.1 appears as homotetramer channel, in astrocytes as homo- and heterotetramer channels together with KIR5.1. In acute MS lesions, KIR4.1 immunoreactivity (IR) was differentially lost on periplaque oligodendrocytes and perivascular astrocytes. In part of acute lesions, complement activation, apoptotic KIR4.1+ glial cells and phagocytes containing KIR4.1+ fragments accompanied loss of glial KIR4.1 IR. Periplaque reactive astrocytes showed enhanced IR for both KIR4.1 and KIR5.1. In chronic active MS lesions, apart from a general loss of oligodendrocytes in the demyelinated area we observed a decrease of astroglial KIR4.1 but not GFAP IR. In chronic inactive and remyelinating MS lesions, KIR4.1 IR was restored on astrocytes and found in a subset of presumably new myelinating oligodendrocytes.

Interpretation:The expression profile of KIR4.1 in glial cells and stage-dependent alterations of KIR4.1 IR in MS lesions are compatible with an immune response against KIR4.1 at least in a subset of MS patients.

If you have antibody responses to Kir4.1 and they can get into the brain yo may have masking of the Kir4.1, which could mask their detection and you could have damage as a result of antibody binding. The importance depends on whether you think this is a major or minor component of MS.

RESULTS:anti-Kir4.1 antibodies were found in 7.5% of MS patients, 4.3% of OND patients and 4.4% of healthy controls. Immunofluorescence analysis did not identify any specific staining.

CONCLUSIONS:we confirmed the presence of anti-Kir4.1 antibodies in MS patients, but at a much lower prevalence than previously reported.

We knew this was arriving since it was documented in ECTRIMS some time ago. The original paper suggested that over 40% of MSers had antibodies against this molecule an ion channel. The frequency mentioned here is about tens times less. So back to the drawing board with regard to the nature of the autoantigen in MS. However, there will be more studies. Neverthe less it further shows there is an autoimmune component in MS.This is science and replication is part of the process. Often it doesn't replicate, but if it is real then people will replicate is and knowledge will move forward.Wonder what Knowledge will come from this weeks AAN meeting in USA?. What do you think are the hot topics...you must have read the abstracts by now.

Tony Blair British Prime Minister for 1997-2007 has been attributed to many things in Wikipedia the Good Friday Agreement, Freedom of Information Act, but few see him as a potential slayer of the British University System with the enforced growth of student numbers leading to unsustainable boom and now bust. Many graduates are left unemployed, with devalued A levels and degrees and crippling debt for the student, which they don't pay. The Labour Party opened the flood gates to a policy first floated by Conservatives. Now the favour is returned.Few see New Labour and Gordon Brown (Prime Minster 2007-2010) as the pilots flying the stealth bomber privatising the NHS by the back door. The Con Dems have done their bit to help steer this on (click here).

No wonder it appears that Labour are in cahoots with the Con-Dems and keeping quiet with apparent cross-party support on backdoor NHS privatisation ......It appears it was a Labour Party Policy generated in the late noughties that allowed people to buy drugs that the Government did not consider cost effective. This has opened the door that pharma are now exploiting. NHS hospitals haveallegedly been told that can increase their private revenue from a few percent of budget to nearly half .........What next?Austerity Britain means that Expensive Drugs are rationed. A two tier of the "haves" and "have nots" is being further created that undermines the principles on which the NHS was founded.

Tuesday, 29 April 2014

Having problems remembering what is going on, Novartis UK has just launched a new iphone Ap apparently Android Ap to Follow Soon for the 4Rs of Relapse (Recognise, Record, Report, Review)

SymTrac™ is a free iPhone app that apparently helps people with MS track general well being and symptoms over time. The data recorded can be viewed in easy-to-read charts and shared with MS specialist teams to enhance consultation time and support decision making.

Designed by people with MS for people with MS, SymTrac™ allows users to make the most of their vital consultation time by providing an objective picture of how their MS has been since their last appointment.

This is an ap to help you remember your signs and symptoms and you can see the video and down load the app or even get the paper version if you are worried about "Big Brother" and Pharma

There is a video by our World Champion paralympian swimmer Stephanie Millward

When she came to the Lab she had the most cracked and manky iphone I have ever seen. Hopefully this means she got a new iphone, so she can more easily text that she got a Gold in Rio, Brazil 2016

Is it user friendly such that it is a pal for life or a toy for a week or two. ProfG and MD do not have an iphone and will have to wait for android version, etc. to test drive it

CoI: None really personally although was given a SymTrac badge at MS life, but TeamG lab has Multiple CoI. This post is for your information and is not an endorsement as I haven't used it...Dear Novartis how about a 5S please :-)

Current treatment modalities for the neurodegenerative disease multiple sclerosis (MS) use disease-modifying immunosuppressive compounds but do not promote repair. Although several potential targets that may induce myelin production have been identified, there has yet to be an approved therapy that promotes remyelination in the damaged central nervous system (CNS). Remyelination of damaged axons requires the generation of new oligodendrocytes from oligodendrocyte progenitor cells (OPCs). Although OPCs are detected in MS lesions, repair of myelin is limited, contributing to progressive clinical deterioration. In the CNS, the chemokine CXCL12 promotes remyelination via CXCR4 activation on OPCs, resulting in their differentiation into myelinating oligodendrocytes. Although the CXCL12 scavenging receptor CXCR7/ACKR3 (CXCR7) is also expressed by OPCs, its role in myelin repair in the adult CNS is unknown.

We show that during cuprizone-induced demyelination, in vivo CXCR7 antagonism augmented OPC proliferation, leading to increased numbers of mature oligodendrocytes within demyelinated lesions. CXCR7-mediated effects on remyelination required CXCR4 activation, as assessed via both phosphorylation specific CXCR4-specific antibodies and administration of CXCR4 antagonists. These findings identify a role for CXCR7 in OPC maturation during remyelination and use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS.

So we have an other target for remyelination. This one is a chemokine (a protein that attracts cells) receptor.These findings identify a role for CXCR7 in OPC maturation during remyelination and are the first to use a small molecule to therapeutically enhance myelin repair in the demyelinated adult CNS.

For those of You not at MS life 2014 the sessions were filmed and are on YouTube so you can search on MS Life 2014 see what every one said. I will post the science ones in the next few days when I have some time.If you want to hear ProfG here is the link

Monday, 28 April 2014

Part of this is a repost from ProfG and follows on from meet and greet at MS Life 2014.

One thing that is clear we need to support all aspects of

Education, Education, and Education

MS Society has, is and needs to be as proactive in this as possible, otherwise the Postcode lottery will remain.

The "Meet the Scientist" session at MS life 2014 was a positive and busy time and provides a good way of giving people of access to science.

ProfWoodRoofe from Sheffield and ProfPaul from Amsterdam talk on a one to one with MSers (Yes we got their permission). The Meet the Scientist is not just a Barts thing

We as scientists need to do more! There are MS Society branches that have never had a visit from any Scientist or Neurologist. To academics out there maybe time to give more back for the support you get or have had from people rattling tins and organise more "public engagement" activities.

To you at MS Society branches or Chapters, You can be the catalyst, why not find out who are your local researchers and them invite them to come and give a talk...We are all big mouths and love an opportunity to spout.

I did one using a portable 5cm Beamer to project slides. But you don't need slides to be able to talk and answer questions. The more you know about your disease and the treatments the better able you will be to make the best choice for yourself.

Education! Education! Education!

This will help beat the postcode lottery in your area.

An MS specialists is likely to more informed and up to date than a generalised Neurologist...Who are you speaking to

It was proposed by ProfG that one way to drive a change in practice is for MSers to ask their neurologist the right questions!

"The following is a list of questions you may want to ask your neurologist when a decision is being made about starting a disease-modifying therapy (DMT) for treating multiple sclerosis (MS)."

6. Do you have active MS? 7. Am I eligible for treatment with a DMT? 8. Do you understand the difference between the treatment strategies of maintenance-and-escalation and induction therapy? 9. Do you understand the concept of treat-2-target of no evident disease activity (NEDA)? BASED ON CONVERSATIONS A GOOD PRACTICAL SESSION OR CLINICAL SPEAK FOR MANY PEOPLE WOULD BE

HOW TO GET A SECOND OPINION....IT IS YOUR RIGHT!

Many MSers at MS life had no trust in their professional carers, "Often the sit back and wait brigade that are so laid back they do nothing"..whilst time is Brain

They may well be taking the standard path but an MRI every nine years is not that good based from our neck of the woods, Maybe "name and shame" (but please don't do it here as I get in enough trouble as it is:-)) is the way to get certain regions to up their game

However, you can be as proactive as possible to avoid this and it doesn't have to mean moving.

If you are not convinced of the actions of your GP or Neurologists you need to seek a second opinion.

If you are in the boonies the chances of an MS specialist being in your locale is more limited but there are big cities all around where MS neuros lurk.

Technology could allow the Neuros to come to your local hospital, will this be away to get rid of the postcode lottery?. A computer camera and a few screens don't cost that much. I have seen it done and work.

"I am disappointed that I could not attend the whole meeting, but I had other teaching commitments that I could not get out of at short notice. After giving my talk I had a lot of questions from the audience and one person asked me how I could justify recommending such a large dose of vitamin D (5,000U per day) to MSers without class 1 evidence. I responded that it was not a large dose, but simply a physiological dose with the aim of making sure MSers are vitamin D replete. I mentioned that there have been studies done showing that much larger doses than 5,000U per day have been done that show that this level of supplementation is safe and this dose is within the current EFSA guidelines. Finally, I mentioned that this recommendation was not my personal recommendation, but I was simply endorsing the recommendations of the Vitamin D Council.

"The following are my slides from my talk. Please note there is no evidence that vD supplements are disease-modifying in MS. The low vD levels in MSers can be due to reverse causation, i.e. MS disease activity results in low vD levels not the other way around. The reverse causation hypothesis, however, is no reason to ignore low vD levels in MSers. The main reason for me recommending vD supplements is for other potential health reasons, in particular bone health. I see little reason to justify leaving MSers in a vD deficient state. This is why I recommend a vD supplementation with the aim of keeping levels above 100nmol/L or 40ng/ml all year round."

MS Life; MSers deserve better services. #MSBlog #MSResearch"As in years past MS Life has re-opened my eyes to what a massive unmet need there is in relation to MS. It is quite clear from discussions I had MSers at MS Life that there is a real disconnect between what I think is the ideal management of MS and what is being provided on the ground. MS services and treatment is simply under resourced. For example, I spoke to three MSers who need FES (functional electrical nerve stimulation) but can't access it as their local commissioners are not prepared to fund it. We don't have a problem with this in London. Why has the postcode lottery resurfaced?""What about DMTs? A large number of MSers I spoke should be on DMTs, but have no access to the necessary services or have been incorrectly told that they were not eligible. So when I got up and gave a talk on DMTs and our strategy of treating-2-target it was pretty ivory tower stuff.""It is clear that the community needs as much education as possible and we need a grass roots revolution so that MSers drive local service development. MSers need to start ask their MS nurse specialists and neurologists probing questions so that they can start a quite revolution.""MS Life is a very positive experience; however, holding it biannually is not enough. We need a focused programme of activity in between this national meeting to make sure change happen." "As promised the following is my presentation from MS Life.

Despite recent advances in development of treatments for multiple sclerosis, there is still an unmet need for more effective and also safe therapies. Based on the modes of action of interferon-beta (IFN-β) and dimethyl fumarate (DMF), we hypothesized that anti-inflammatory and neuroprotective effects may synergize in experimental autoimmune encephalomyelitis (EAE).METHODS:EAE was induced in C57BL/6 mice by immunization with MOG35-55-peptide. Mouse IFN-β was injected s.c. every other day at 10.000IU, and DMF was provided at 15mg/kg by oral gavage twice daily. Control mice received PBS injections and were treated by oral gavage with the vehicle methylcellulose. Mice were scored daily by blinded observers and histological, FACS and cytokine studies were performed to further elucidate the underlying mechanism of action.RESULTS:Combination therapy significantly ameliorated EAE disease course in comparison to controls and monotherapy with IFN-β. Histological analyses showed a significant effect on axon preservation with almost twice as much axons present in inflamed lesions as compared to control. Remarkably, the effect on axonal preservation was more pronounced under combination therapy than with both monotherapies. Neither monotherapy nor combination therapy demonstrated modulation of cytokines and frequency of antigen presenting cells.DISCUSSION: Combination of IFN-β and DMF resulted in greater beneficial effects with improved tissue protection as compared to the respective monotherapies. Further combination studies of these safe therapies in human disease are warranted.

In this study they used a dose of interferon beta and a dose of a BG-12 (Tecfidera) homologue which were not totally effective in controlling EAE and then put them together. They got a better effect on clinical disease and unsurprisingly they did not get much nerve loss.

So Biogen Idec can rub its hands together and test two expensive drugs in MS, one anti-inflammatory and the other anti-inflammatory (with suspected neuroprotective effects-but does it get in the brain?).

This could be used to justify a trial using optimised doses of BG-12 and beta interferon, neither of which yet to robust actions on brain atrophy, unlike some other DMT.

So is this result unexpected?. It says that the drugs are working either on different mechanisms or they add together to give more punch against a disease mechanism.

Teva has done exactly the same experiment (check out their patents) with laquinimod and all other chemical DMT. The two together work better than either sub-optimal drug individually....Justification of patent and trial.

As the inflammatory response causes nerve loss, get rid of the inflammatory response and you get more neuroprotection...what would you see with a fully optimised single treatment...No disease and no nerve loss? So it could save nerves even if the drug does not get into the brain.

In this study they claim synergism of the two drugs. Synergism is a thing that we often hear. However is the effect an additive effect of two drugs or real synergism, where the sum of the two parts are greater than simple addition.

However, the problem with EAE scoring is that the EAE scale is probably not linear so the pathological difference between a score 0 and a score 1 may not be the same as the difference between a score 3 and a score 4. So we can have (a + a = c) or is it (a + a = m). So it is difficult to say if there is true synergism. What do you think in this case?

It makes some sense to combine lower doses of drugs as it may reduce the side-effects of both, however adding one immune suppressive drug to another may actually increase the chances of side effects, those of each drug plus the combined effect because they may be a greater immunosuppressive agent and so increase the risks of serious adverse events.

If you put the effects of the two drugs against an effective dose of one DMT would it really be better?...In MS maybe, in acute EAE?

The vast majority of cellular proteins are degraded by the 26S proteasome after their ubiquitination. Here, we report that the major component of the myelin multilayered membrane sheath, myelin basic protein (MBP), is hydrolyzed by the 26S proteasome in a ubiquitin-independent manner both in vitro and in mammalian cells. As a proteasomal substrate, MBP reveals a distinct and physiologically relevant concentration range for ubiquitin-independent proteolysis. Enzymatic deimination prevents hydrolysis of MBP by the proteasome, suggesting that an abnormally basic charge contributes to its susceptibility towards proteasome-mediated degradation. To our knowledge, our data reveal the first case of a pathophysiologically important autoantigen as a ubiquitin-independent substrate of the 26S proteasome.

Proteasomes are protein complexes inside cells the are located in the nucleus and the cytoplasm.The main function of the proteasome is to degrade unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Enzymes that carry out such reactions are called proteases. Proteasomes are part of a major mechanism by which cells regulate the concentration of particular proteins and degrade misfolded proteins. The degradation process yields peptides of about seven to eight amino acids long, which can then be further degraded into shorter amino acid sequences and used in synthesizing new proteins. Proteins are tagged for degradation with a small protein called ubiquitin. The tagging reaction is catalyzed by enzymes called ubiquitin ligases. Once a protein is tagged with a single ubiquitin molecule, this is a signal to other ligases to attach additional ubiquitin molecules. The result is a polyubiquitin chain that is bound by the proteasome, allowing it to degrade the tagged protein.

In structure, the proteasome is a cylindrical complex containing a "core" of four stacked rings forming a central pore. Each ring is composed of seven individual proteins. The inner two rings are made of seven β subunits that contain three to seven protease active sites. These sites are located on the interior surface of the rings, so that the target protein must enter the central pore before it is degraded. The outer two rings each contain seven α subunits whose function is to maintain a "gate" through which proteins enter the barrel. These α subunits are controlled by binding to "cap" structures or regulatory particlesthat recognize polyubiquitin tags attached to protein substrates and initiate the degradation process. The overall system of ubiquitination and proteasomal degradation is known as the ubiquitin-proteasome system.

So myelin basic protein does get degraded by this pathway. Many people believe that myelin basic protein is an important target in MS. However there is limited poof that this is indeed the case.

Attempts to tolerise the immune system against MBP has usually been met with failure or sometimes disease worsening (which I guess provides the best proof for some role).

T-cell migration across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Live cell imaging studies demonstrated that P-selectin glycoprotein ligand-1 (PSGL-1) and its endothelial ligands E- and P-selectin mediate the initial rolling of T cells in brain vessels during EAE. As functional absence of PSGL-1 or E/P-selectins does not result in ameliorated EAE, we speculated that T-cell entry into the spinal cord is independent of PSGL-1 and E/P-selectin. Performing intravital microscopy, we observed the interaction of wild-type or PSGL-1-/- PLP-specific T cells in inflamed spinal cord microvessels of wild-type or E/P-selectin-/- SJL/J mice during EAE. T-cell rolling but not T-cell capture was completely abrogated in the absence of either PSGL-1 or E- and P-selectin, resulting in a significantly reduced number of T cells able to firmly adhere in the inflamed spinal cord microvessels, but did not lead to reduced T-cell invasion into the CNS parenchyma. Thus, PSGL-1 interaction with E/P-selectin is essential for T-cell rolling in inflamed spinal cord microvessels during EAE. Taken together with previous observations, our findings show that T-cell rolling is not required for successful T-cell entry into the CNS and initiation of EAE.

The way cells exit the blood was first seen by looking at cells (neutrophils) coming out of blood in the gut as the vessels were easy to dissect and put under a microscope. There was seen that blood cells are slowed down they contact selectins (carbohydrate molecules) and start rolling before they tether and migrate. However, this study shows that they don't need to roll to cell into the brain.

Chronic cerebrospinal venous insufficiency (CCSVI) is a vascular condition characterized by morphological alterations involving efferent cerebral vascular paths. CCSVI has been implicated as a contributing factor to multiple sclerosis (MS) but this theory is highly controversial. We report three cases of CCSVI patients with MS who had undergone internal jugular veins (IJVs) angioplasty to restore vessels patency. All patients reported significant symptomatic improvement after angioplasty until symptoms recurred following restenosis of the treated IJVs. Surgical IJVs reconstruction was performed. Patients' symptoms gradually improved and the benefits were maintained at the one-year follow up.

Some positive news on the day, I will no doubt meet a few fans of the procedure at MS life 2014. If it is so clear cut, then why have the trials so far been unconvincing or stopped? Hopefully we will soon hear from more definitive trials.

Friday, 25 April 2014

Protecting Brain: do we have a responsinility to protect your brain? #ClinicSpeak #MSBlog #MSResearch

"Protecting Brain! Do we have a responsibility to protect brain? Now that we have therapies that have an impact on end-organ damage, i.e. they delay or slow down brain volume loss should we be targeting this as an outcome in MS treatment?"

"The following study shows in MS, as has been shown for Alzheimer's disease, that brain reserve capacity protects you to the some extent from MS-related cognitive decline. Dare I refer to this problem as a preventable dementia? Apart from DMTs, in particular high-efficacy DMTs, is there anything else you can do to reduce cognitive decline? Yes, you should try and optimise your brain health. The lessons for you are the same general lessons that apply to the whole population. The following is a quick list I have put together:

Keep yourself mentally active; I am not sure that the evidence of brain training is robust enough to be prescribed to MSers, but it makes sense.

Stop smoking.

Improve your sleep hygiene.

Review what drugs your are on; many of the drugs we prescribe to treat the symptoms of MS make cognitive impairment worse.

Actively manage any co-morbidities you may have, in particular high blood pressure, diabetes, obesity and high cholesterol.

Depression, low mood, anxiety and stress; if you are depressed or anxious please seek advice and treatment. Depression and anxiety affects cognitive function. Try and manage levels of stress.

Invest in social capital; keep working on your relationships with your family and friends. Social isolation is not good for cognitive functioning and the factors that impact on cognition.

If you have cognitive problems already you may want to enrol in a cognitive rehabilitation programme. If this is not possible you could try the on-line programme, Staying Smart, that the MS Trust run."

CONCLUSION: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with MS.

I was recently listening to an MSer, about where they go to get their info about MS. Many people use the Internet for info....be carefulDo you go to the info sites provided by Pharma companies? Are they Really the "Devil"?Do they have an Image problem?Do you get the best info from your neuro or MS Nurse-the Angel?

This Weekend April 26-27, there is MS life Meeting in Manchester. Maybe you can get the infor from the horses mouth. There are going to be some Neuros present....Dr. Coles for Cambridge is there. Will he present their data on the long term follow-up of early MSers on Alemtuzumab?Do they convert to SPMS? Maybe ask the question and you may get an answer that you want to know?

BACKGROUND:People with multiple sclerosis (MS) are confronted with a number of important uncertainties concerning many aspects of the disease. Among others, these include diagnosis, prognosis, disease course, disease-modifying therapies, symptomatic therapies and non-pharmacological interventions. It has been shown that people with MS demand adequate information to be able to actively participate in medical decision making and to self-manage their disease. On the other hand, it has been found that patients' disease-related knowledge is poor. Therefore, guidelines have recommended clear and concise high-quality information at all stages of the disease. Several studies have outlined communication and information deficits in the care of people with MS and, accordingly, a number of information and decision support programmes have been published.OBJECTIVES: To evaluate the effectiveness of information provision interventions for people with MS that aim to promote informed choice and improve patient-relevant outcomes.SELECTION CRITERIA: Randomised controlled trials, cluster randomised controlled trials and quasi-randomised trials comparing information provision for people with MS or suspected MS (intervention groups) with usual care or other types of information provision (control groups) were eligible.MAIN RESULTS: Ten randomised controlled trials involving a total of 1314 participants met the inclusion criteria and were analysed. The interventions addressed a variety of topics using different approaches for information provision in different settings. Topics included disease-modifying therapy, relapse management, self-care strategies, fatigue management, family planning and general health promotion. The interventions contained decision aids, educational programmes, self-care interventions and personal interviews with physicians. All interventions were complex interventions using more than one active component, but the number and extent of the intervention components differed markedly between studies. The studies had a variable risk of bias. We did not perform meta-analyses due to marked clinical heterogeneity. All four studies assessing MS-related knowledge (524 participants; moderate-quality evidence) detected significant differences between groups as a result of the interventions indicating that information provision may successfully increase participants' knowledge. There were mixed results from four studies reporting effects on decision making (836 participants; low-quality evidence) and from five studies assessing quality of life (605 participants; low-quality evidence). There were no adverse events in the six studies reporting on adverse events.AUTHORS' CONCLUSIONS: Information provision for people with MS seems to increase disease-related knowledge, with less clear results on decision making and quality of life. There seem to be no negative side effects from informing patients about their disease. Interpretation of study results remains challenging due to the marked heterogeneity of the interventions and outcome measures.

BACKGROUND: Autologous haematopoietic stem cell transplantation (HSCT) is a viable option for treatment of aggressive multiple sclerosis (MS). No randomised controlled trial has been performed, and thus, experiences from systematic and sustained follow-up of treated patients constitute important information about safety and efficacy. In this observational study, we describe the characteristics and outcome of the Swedish patients treated with HSCT for MS.METHODS:Neurologists from the major hospitals in Sweden filled out a follow-up form with prospectively collected data. Fifty-two patients were identified in total; 48 were included in the study and evaluated for safety and side effects; 41 patients had at least 1 year of follow-up and were further analysed for clinical and radiological outcome. In this cohort, 34 patients (83%) had relapsing-remitting MS, and mean follow-up time was 47 months.RESULTS: At 5 years, relapse-free status was 87%; MRI event-free status 85%; expanded disability status scale (EDSS) score progression-free status 77%; and disease-free status (no relapses, no new MRI lesions and no EDSS progression) 68%. Presence of gadolinium-enhancing lesions prior to HSCT was associated with a favourable outcome (disease-free status 79% vs 46%, p=0.028). There was no mortality. The most common long-term side effects were herpes zoster reactivation (15%) and thyroid disease (8.4%).CONCLUSIONS: HSCT is a very effective treatment of inflammatory active MS and can be performed with a high degree of safety at experienced centres.

BACKGROUND:Haematopoietic stem cell transplantation (HSCT) is a new window to therapy of many diseases. From March 1991 through April 2011, a total of 3237 HSCT were performed in the Haematology-Oncology and Stem Cell Transplantation Research Center. Here we report 20 years experience of HSCT.PATIENTS AND METHODS: Totally, 3237 patients were undergone HSCT. Of these transplants, 2205 were allogeneic stem cell transplantation, 1016 autologous and 16 syngeneic. RESULTS: About 78.2% of the patients (2530 of 3237) remained alive between one to 211 months after stem cell transplantation. Nearly, 21.8% (707) of our patients died after stem cell transplantation. The main causes of death were relapse, infection, haemorrhagic cystitis, graft-versus- host disease and etc.CONCLUSIONS: HSCT has been successfully adapted in routine clinical care.

The patient's own stem cells are harvested and stored temporarily while high doses of chemotherapy and biologics are used to destroy the auto-destructive immune system. The immune system is regenerated from the infused autologous hematopoietic stem cells. Increasing clinical experience has refined patient selection criteria and management in the peri-transplant period leading to a reduction in treatment-related complications. HSCT, when used to treat patients with aggressive highly active multiple sclerosis, can reduce or eliminate ongoing clinical relapses, halt further progression, and reduce the burden of disability in some patients, in the absence of chronic treatment with disease-modifying agents. The top 10 lessons learned from the growing experience using HSCT for the treatment of multiple sclerosis are discussed.

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and anti-thymocyte globulin were followed bytransplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening ≥1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of ≤6.0; four of them had not failed treatment at last study visit (one of them had failed). OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.

Thursday, 24 April 2014

Charity urges Government to take action on World Day for Laboratory Animals

Today (24 April) is World Day for Laboratory Animals and the RSPCA is calling on the UK Government to commit to ending the use of animals in experiments that cause ‘severe’ suffering.

Scientific procedures using animals in the UK are classified as ‘mild’, ‘moderate’ or ‘severe’, and while any level of suffering is a concern for the RSPCA, ending severe suffering is a top priority.

The amount of pain or distress experienced by each lab animal depends on the kind of research being done, and also on how much effort has been made to reduce or avoid suffering. Each year, animals are involved in experiments categorised as ‘severe’, which cause severe pain, suffering or distress, or ‘severe impairment of their well being or general condition’. The exact number of animals experiencing this will be unknown, until changes in reporting take effect next year - but even a 2% level of severe suffering will involve tens of thousands of animals.

This is a major animal welfare and ethical issue that the RSPCA believes must be addressed as a matter of urgency. We are urging the UK Government to take a policy decision not to license animal experiments in which animals would be expected to experience ‘severe’ suffering.

RSPCA Senior Scientist Dr Penny Hawkins said: “A Government decision not to allow severe suffering would truly focus the minds of those using animals in research, or who fund animal use, on ensuring that absolutely everything possible is done to avoid severe pain, suffering, distress or lasting harm.

“People often say that they work to ‘high welfare standards’ and do not want to cause severe suffering, so they should view a decision not to license these experiments as a welcome challenge to help them make real progress towards more humane science.”

RSPCA calls for end of MS Animal Research. They do not say this directly but this is what they mean as Animal Experiments on Multiple Sclerosis are considered to be "Severe" . Therefore these types of experiments could leave these shores.

Hurray you may say.....but where does this work move to?....

To places where they hang animals upside down by their tail for months.....?

BACKGROUND Genome-wide association studies (GWAS) have identified over 100 germline variants that influence susceptibility to multiple sclerosis, most of which map within or near to genes with immunological function. However, the role of somatic mutations in multiple sclerosis has not been investigated.OBJECTIVE:The objective of this paper is to explore the role that somatic mutations might play in the development of multiple sclerosis.METHODS:We exome-sequenced in total 21 individual CD4+ lymphocytes isolated from cerebrospinal fluid of two patients. In addition we sequenced DNA from the patients' peripheral blood to serve as germline reference.RESULTS:In comparison with the respective germline sequence, each cell differed at an average of 1784 positions, but as anticipated subsequent analysis confirms that most, if not all, of these potential mutations are likely to represent artefacts generated during the amplification of a single genome and/or by sequencing. Fifty-six of the potential mutations were predicted to have likely functional effects on genes that have previously been implicated by GWAS, including three in the CD6 gene.CONCLUSION: More robust methods applied to larger numbers of cells will be needed to define the role of somatic mutations.

When DNA is made into a protein the introns (non-coding bits) of DNA are removed to have RNA made up of exons (coding bits) of the DNA, this can be sequenced to see what proteins are likely to be made.

Exome sequencing (also known as targeted exome capture) is an efficient strategy to selectively sequence the coding regions of the genome as a cheaper but still effective alternative to whole genome sequencing. Exons are short, functionally important sequences of DNA which, together, represent only slightly more than the portion of the genome that is actually translated into protein. Exons are flanked by untranslated regions (UTR) that are usually not included in exome studies. In the human genome there are about 180,000 exons. These constitute about 1% of the human genome.

They were looking for mutations (switches of the original DNA sequence) when CD4 T cells made protein but the was loads of mistakes in the technology, so the technology needs improving. The may have found some in CD6. What does it mean I don't know?, but this introduces you to the idea of technology.

So once every body has been genome-sequenced we can do it again and again for every, cell type at different time points.

Natalizumab is not 100% effective in stopping immune responses within the CNS #MSBlog #MSResearch

"The following study uses a very old technique of looking for the production of specific antibodies within the central nervous system (CNS), or intrathecal compartment (within the membranous coverings of the brain), to help diagnose PML. The investigators used a so called JCV antibody index to detect antibody production within the CNS against the JC virus. The way this technique works is that they have to normalise the levels of anti-JCV antibodies against a ratio of other proteins to account for a leaky blood brain barrier, which is the norm in MSers. This correction allows you to create a virus specific antibody index; an index greater than 1.5 indicates that there is production of anti-JCV antibodies within the CNS. It implies that there are B cells and plasma cells in the brain and spinal cord that are making anti-JCV antibodies. We know that this occurs commonly in other viral infections of the brain, for example with mumps, measles, rubella and herpes infections. The investigators found that in 70% of MSers who had PML diagnosed using MRI and the detection of virus specific DNA had an index greater than 1.5. This means that 30% did not. In general a diagnostic test has to be at least 80% sensitive (detecting PML) and specific (excluding PML) before it can be used clinically. I am therefore not sure about their conclusion that the index can be used to help diagnose PML. More work needs to be done on this assay. A factor that needs to be considered is the mode of action of natalizumab; it blocks lymphocyte trafficking into the CNS therefore it potentially could prevent and adequate CNS B-cell response which may explain why the only 70% had an index > 1.5 and not a figure closer to 100%. The good news is that their data suggests that there is some immune response to the virus in MSers with PML on natalizumab. This indicates that natalizumab is not 100% effective at blunting the immune responses within the CNS and may explain why some MSers with PML have low-grade immune reconstitution inflammatory syndrome (IRIS) despite still being on natalizumab and that most biopsies done when MSers are on natalizumab show inflammatory cell infiltrates. This data suggests we may need more effective cell trafficking blockers that natalizumab to treat MS. This is the first time I have thought about actually improving on the efficacy that natalizumab provides. Interesting?"

Background: Progressive multifocal leukoencephalopathy (PML), caused by JC virus (JCV), can occur in MSers receiving natalizumab for MS. JCV detection by quantitative polymerase chain reaction (qPCR) in cerebrospinal fluid (CSF), or brain biopsy is required for probable or definite diagnosis of PML. However, in some MSers only low levels of JCV-DNA (<100 copies/ml) are present in CSF, making the diagnosis challenging.

Objective: To assess the complementary value of a CSF JCV antibody index (AIJCV ) in the diagnosis of natalizumab-associated PML.

Methods: In 37 cases of natalizumab-associated PML and 89 MSers treated with natalizumab without PML AIJCV was assessed. Sera and CSF were tested in a capture ELISA, using JCV-VP1 fused to glutathione S-transferase (GST) as antigen. Albumin levels and total IgG concentration were determined by immunonephelometry, and the AIJCV was calculated as published.

Results: Twenty-six of 37 (70%) patients with natalizumab-associated PML exhibited an AIJCV >1.5, while this was seen in none of the controls (p<0.0001). At time of the first positive qPCR for JCV-DNA, 11/20 (55%) of MSers with natalizumab-associated PML had an AIJCV >1.5. JCV-DNA levels of <100 copies/ml were seen in 14/20 (70%) of these MSers of which 8 (57%) demonstrated an AIJCV >1.5.

Interpretation: Determination of the AIJCV could be an added tool in the diagnostic workup for PML and should be included in the case definition of natalizumab-associated PML.

Wednesday, 23 April 2014

Vaccinations on highly-effective DMTs; what you need to know. #ClinicSpeak #MSBlog #MSResearch

"This study below shows that MSers treated with natalizumab mount an immune response to both a memory, or recall, vaccine (tetanus) and a new vaccine challenge (keyhole limpet hemocyanin). This information is important to MSers in that they can have vaccines and be confident that they can mount an immune response to the vaccine and hopefully be protected from the relevant infection. Please note this study only looked at so called component, or inactivated vaccines, and not live vaccines. Live vaccines are composed of live attenuated viruses and require the virus to cause and active infection within the body for the immune system to respond. Examples of live vaccines include the oral polio vaccine and yellow fever. I am not aware of any data on live vaccines and natalizumab treatment and would advise against them. These viruses are neurotropic and hence infect the nervous system. If the do infect the nervous system you need your immune system to be intact to be able to find and attack the virus. We know that natalizumab prevents the trafficking of lymphocytes into the brain and spinal cord and hence your immune system will not be able to seek and destroy the virus. For similar reasons I warn MSers under my care about travel to places that are associated with exotic infections that can infect the brain that cannot be covered by a inactivated or component vaccine; examples include dengue fever and yellow fever."

"Do the other high efficacy agents have the same effect on vaccination? Fingolimod blunts your recall and novel immune response to component vaccines. Live vaccines are contra-indicated if you are on fingolimod. With alemtuzumab vaccinations are contra-indicated until 3 months after the last course of treatment and your blood counts have recovered enough to mount an immune response. Some preliminary data (abstract below) suggests that immune responses to both component and live vaccines post-alemtuzumab are intact. This is not surprising as once your immune system recovers post-alemtuzumab it is capable of mounting an immune response. Confirmatory data on vaccination post-alemtuzumab is required as the study below is very small."

"I personally think immune responses to vaccinations is one factor that needs to be considered when choosing a therapy; this is particularly important for MSers who like to travel. You may also want to delay starting a treatment until you have had specific vaccines. If you have any specific queries regarding vaccinations and the treatment you are on you should discuss this with your neurologist."

Methods: Natalizumab-naive relapsing MSers were randomized (1:1; n=30 per group) to receive TT and KLH immunizations either without natalizumab treatment (control) or after 6 months of natalizumab treatment (natalizumab group). An adequate response to immunization was defined as an increase to at least twofold in specific serum immunoglobulin G (IgG) 28days after the first immunization.

Results: All evaluable MSers achieved protective levels of anti-TT IgG antibodies, and the proportion of responders to this recall antigen, as well as to primary immunization with KLH, was similar in the presence and absence of natalizumab.

Conclusion: This indicates that natalizumab treatment does not appear to affect responses to primary or secondary immunization in a clinically meaningful way.

OBJECTIVE: To determine the immunocompetency of patients with multiple sclerosis treated with the lymphodepleting humanized monoclonal antibody alemtuzumab.

METHODS: In this pilot case-control study, we assessed immunocompetence in 24 patients after alemtuzumabtreatment by measuring antibody responses to 3 vaccines (diphtheria, tetanus, and poliomyelitis vaccine, Haemophilus influenzae type b and meningococcal group C conjugate vaccine, and pneumococcal polysaccharide vaccine). In 20 patients, antibodies to common viruses (mumps, rubella, varicella-zoster, and Epstein-Barr virus) were measured before alemtuzumab treatment, then at 1 and 9-11 months after treatment. Results were compared with well-defined historical controls.

RESULTS: Serum antibodies against common viruses remained detectable after treatment, and vaccine responses were normal to T-cell-dependent recall antigens (tetanus, diphtheria, and polio), a T-cell-dependent novel antigen (meningococcus C), and T-cell-independent antigens (pneumococcal). There was no evidence for a diminished response to vaccinations in 5 patients studied within 6 months of alemtuzumab treatment.

CONCLUSION: In this small historically controlled pilot study, we demonstrated i) retained humoral immunologic memory (in the form of antibodies against common viruses and response to recall antigens), and ii) the retained ability to mount a humoral immune response against a novel antigen after treatment with alemtuzumab.

The mechanism of action of natalizumab has immunosuppressive properties and it is not yet investigated if treatment with natalizumab affects the immunological response to vaccination. This study aims to investigate the ...

The authors conclude that vaccination response is not lost post-alemtuzumab treatment and immunity remains if you have been vaccinated previously. However the numbers are small, and so it is difficult to draw wide ranging ...

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